Insulin sensitivity: modulation by nutrients and inflammation.

Abstract

Insulin resistance is a major metabolic feature of obesity and is a key factor in the etiology of a number of diseases, including type 2 diabetes. In this review, we discuss potential mechanisms by which brief nutrient excess and obesity lead to insulin resistance and propose that these mechanisms of action are different but interrelated. We discuss how pathways that "sense" nutrients within skeletal muscle are readily able to regulate insulin action. We then discuss how obesity leads to insulin resistance via a complex interplay among systemic fatty acid excess, microhypoxia in adipose tissue, ER stress, and inflammation. In particular, we focus on the hypothesis that the macrophage is an important cell type in the propagation of inflammation and induction of insulin resistance in obesity. Overall, we provide our integrative perspective regarding how nutrients and obesity interact to regulate insulin sensitivity.

Obesity results in an increased flux of free fatty acids into the circulation and uptake by the myocyte or hepatocyte. Activated fatty acids (i.e., fatty acyl-CoAs) are “metabolized” primarily via one of two pathways, oxidation or storage. When fatty acid flux exceeds the ability of these pathways to dispose of fatty acyl-CoAs, intermediaries of fatty acid metabolism (e.g., DAG, PA, LPA, ceramide) accumulate. In turn, these fatty acid intermediates can activate a number of different serine kinases that can negatively regulate insulin action. Ceramide can also impair insulin action through interactions with PKB/Akt. An inability to completely oxidize fatty acids through β-oxidation, which leads to an accumulation of acylcarnitines, has also been hypothesized to cause insulin resistance, although the precise mechanisms leading to insulin resistance are, to date, unknown. AGPAT, acylglycerol-3-phosphate acyltransferase; PAP, PA phosphohydrolase.

Nutrient excess, weight gain, and ensuing obesity result in expansion of adipose tissue mass and adipocyte size. With this expansion, total free fatty acid release into the circulation is increased and oxygen delivery to the adipocyte is decreased. The combination of microhypoxia and nutrient excess leads to induction of HIF-1 and the downstream target genes as well as ER stress within the adipocyte. This can lead to the eventual death of the adipocyte as well as a characteristic inflammatory response. The inflammatory response includes increased production and release of proinflammatory cytokines/chemokines and the recruitment of bone marrow–derived macrophages (Mϕ). These macrophages are of the M1 activation/polarization state and are highly inflammatory in nature. Once recruited, these macrophages release proinflammatory cytokines, which work in a paracrine manner to activate the intracellular proinflammatory pathways (e.g., JNK and IKK) in neighboring cells and possibly through endocrine mechanisms in distal tissues. In a feed-forward cycle, activation of macrophages promotes the recruitment and infiltration of additional macrophages into adipose tissue. This results in cell autonomous insulin resistance in adipocytes and liver, exacerbation of the inflammatory state, and systemic insulin resistance. With obesity, there is also increased fat accumulation within skeletal muscle, and these intermuscular fat depots becomes infiltrated with proinflammatory macrophages, which may cause paracrine-like insulin resistance in skeletal muscle. In parallel with these inflammation-related changes, alterations in fatty acid metabolism can lead to the accumulation of fatty acid intermediates with the liver and skeletal muscle, which can cause insulin resistance via mechanisms outlined in Figure . In addition, fatty acids can serve as ligands to broadly activate inflammatory pathways in Kupffer cells and ATMs (e.g., via TLR2/TLR4 signaling pathways).